Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV001187891 | SCV001354804 | uncertain significance | Cardiomyopathy | 2023-03-09 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with isoleucine at codon 478 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PRKAG2-related disorders in the literature. This variant has been identified in 2/250832 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Invitae | RCV001231602 | SCV001404130 | uncertain significance | Lethal congenital glycogen storage disease of heart | 2022-11-21 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRKAG2 protein function. ClinVar contains an entry for this variant (Variation ID: 925757). This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 478 of the PRKAG2 protein (p.Val478Ile). |
| New York Genome Center | RCV003336321 | SCV004046517 | uncertain significance | Hypertrophic cardiomyopathy 6 | 2023-04-03 | criteria provided, single submitter | clinical testing | The c.1432G>A p.(Val478Ile) missense variant identified in the PRKAG2 gene has not been reported in affected individuals in the literature, but has been reported as a Variant of Uncertain Significance in the ClinVar database [Variation ID: 925757]. The c.1432G>A variant is observed in 6 out of 559,546 heterozygous alleles (0.00001 minor allele frequency, no homozygote) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.1432G>A variant is located in exon 13 of this 16-exon gene and is predicted to replace a highly conserved valine residue with isoleucine at position 478 within the CBS 3 domain of the encoded protein [UniProt ID: Q9UGJ0]. The c.1432G>A variant is located 5 nucleotides away from exon13/intron13 junction. In silico predictions are not in favor of the variant’s damaging effect [REVEL = 0.417, SpliceAI deltascore = 0.02]; however, functional studies to support or refute these predictions have not been reported. Based on the available evidence, the c.1432G>Ap.(Val478Ile) missense variant identified in the PRKAG2 gene is reported as a Variant of Uncertain Significance. |